This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this project has been to elucidate the pathophysiologic mechanisms of abnormal behaviors in Parkinson's disease (PD) in view of developing new therapeutic tools. A central specific aim of the project is to characterize basal ganglia functional alterations as shown by changes of regional neuronal activity. This project has made great progress in this specific aim, and during the last period we have analyzed most electrophysiology data of single cell recording from the striatum and the external segment of the globus pallidus (GPe). In the external pallidum, firing rates are congruent with findings of neuronal activity in the striatum. Our results are starting to unveil important functional changes in basal ganglia as a result of chronic parkinsonism that pose radical revisions of the classic models of Parkinson's disease. During the past year, we have also found significant alterations in the pattern of striatal neuronal activity that correlate well with specific motor behaviors such as levodopa-induced dyskinesias. These findings contribute critical information to the pathogenesis of abnormal motor behaviors in PD, and lead us to new therapeutic hypotheses based on our physiology findings. Our studies have posited that drugs acting on the cannabinoid system may have an impact on parkinsonian symptoms because of the cannabinoid CB1 receptor-mediated effects upon the glutamate release in the striatum that appears to be highly augmented in the chronic parkinsonian state. We are currently testing the striatal effects of specific cannabinergic agents in chronic parkinsonian monkeys.